Figure 7 The structures of 5fluoruracil and mitomycin C

verteporfin (Figure 5) as the active agent. In PDT, a verteporfin-containing solution is administered intravenously to the patient, and the verteporfin apparently preferentially collects in the endothelium of neoangiogenic capillaries. About 15 min later a red laser is shone into the AMD-affected eye(s), and resultant photon absorption by the porphyrin produces an electronically excited state that transfers energy to oxygen to produce reactive oxygen species. Oxidation of molecules in the endothelium ensues, leading to vessel obstruction and collapse of the affected capillaries. The dosing frequency is approximately once every 3 months.

PDT is different from and offers several distinct advantages over laser retinal photocoagulation, which was previously the only treatment option for wet AMD. The latter case involves thermal destruction of the neovascular lesion with a laser, which because of the vagaries of laser targeting and thermal energy transfer leads to collateral destruction of some surrounding tissue. The destroyed tissue permanently loses visual functionality, and patients frequently experience an immediate drop in visual acuity. PDT, however, involves the use of a 'cold' laser that only directly transfers energy to the porphyrin. The reactive oxygen species produced as a downstream event is likely to react only with the closest surrounding tissue, leading to less collateral damage. The apparent preferential accumulation of verteporfin in newly formed capillaries also helps limit unwanted tissue destruction.

There are several limitations of PDT however. First, relative to placebo this therapy only slows the rate of loss, but does not improve visual acuity. Second, the dosing regimen using an intravenous infusion of verteporfin over a 10-15 minute period can be inconvenient. Third, after treatment the patient is somewhat photosensitive and is advised to avoid sun exposure for several days. Fourth, like laser photocoagulation, PDT works not by interrupting on the molecular level a fundamental mechanism of angiogenesis (e.g., by inhibiting an overexpressed receptor) but instead uses a massive chemical insult to destroy the lesion. As such it seems unlikely that the disease pathology/progression can be reversed or even significantly slowed. Fifth, the FDA currently approves PDT using verteporfin for the treatment of only the predominantly classic subtype of wet AMD, although there are clinical trials evaluating its use for prevention of disease progression in the minimally classic and occult sub-types.66

The second approved therapy uses a solution of the VEGF-binding aptamer pegaptanib sodium. Pegaptanib, a 28-residue, RNA-based oligonucleotide that is capped on both ends with a residue containing polyethylene glycol, has a molecular mass of approximately 50 kDa. The pegaptanib solution is injected into the vitreous humor of the patient every 6 weeks, and is approved for all three subtypes of wet AMD (classic, minimally classic, and occult). In phase III clinical trials AMD patients treated with 0.3 mg of pegaptanib solution over either a 1- or 2-year period experienced less loss of visual acuity than did patients receiving placebo.67

Pegaptanib is thought to work by binding with high affinity to the VEGF165 isoform, which is believed to be the most pathologically important isoform.68 Therefore VEGF165 is prevented from binding to and activating the VEGF receptor. With the angiogenic signal thus blocked, new capillaries stop forming.

The main advantage of interfering with VEGF-VEGF receptor binding in general and pegaptanib in particular is that a fundamental pathological pathway is intercepted. Since pegaptanib is an aptamer, in theory there should be fewer problems with adverse immune system effects as compared with an antibody. The highly selective action of the drug suggests a favorable side-effect profile, at least with respect to off-target effects.

The disadvantages to pegaptanib therapy arise from drug specific and drug class considerations. Pegaptanib is administered by intravitreal injection, which is inconvenient, requires highly skilled delivery by an ophthalmologist, and in clinical trials has demonstrated a higher rate of intraocular infection (endophthalmitis) and retinal detachment than in controls.67 It is not known if pegaptanib's lack of binding to other VEGF isoforms lessens its effectiveness as compared with pan-isoform binders like the anti-VEGFantibody ranibizumab (see Section Pegaptanib does not improve visual acuity or arrest its degradation, which would be ultimately desirable.

Efficient blockade of the VEGF axis in general may hold pitfalls. VEGF functions as a protective agent in animal models of several neurodegenerative diseases, e.g., stroke (see 6.10 Stroke/Traumatic Brain and Spinal Cord Injuries)

and amyotrophic lateral sclerosis (see 6.09 Neuromuscular/Autoimmune Disorders).69 Genetically induced enhancement of VEGF production is being investigated as a treatment for coronary vascular disease.70 Thus, direct interruption of the VEGF axis could inhibit the body's endogenous repair response to ocular neuronal and vascular deficiencies, which may occur with heightened frequency in AMD. In a related fashion, if excess VEGF production occurs as a response to perceived hypoxia in the retina, it is not clear that the underlying conditions causing the hypoxia are resolved when VEGF activity is inhibited.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

Get My Free Ebook

Post a comment